Potential Molecular Biomarkers of Treatment Response in Rheumatoid Arthritis

VBCR - May 2012, Volume 1, No 2 - Personalized Medicine in Rheumatology

By Sy Schlager, MD, PhD
The effective use of biologic disease-modifying antirheumatic drugs (DMARDs) has dramatically improved the treatment of rheumatoid arthritis (RA) over recent years. However, for at least 33% of patients with RA, tumor necrosis factor (TNF) inhibitor therapy produces an inadequate clinical response. Indeed, responses to biologic agents vary across different patient populations, especially with respect to differences in duration and reversibility of disease.

Many studies have shown that although TNF antagonists improve clinical signs and symptoms of RA in patients in whom conventional DMARDs had produced inadequate responses, the American College of Rheumatology (ACR) 20 response criteria (ACR20) for TNF inhibitors generally range from 20% to 40% response rates. Similarly, in those with an inadequate response to TNF inhibitors, the newer biologic agents can achieve ACR20 response rates at 24 weeks, ranging from 17% with golimumab (Simponi) to 40% with tocilizumab (Actemra). Moreover, only rituximab (Rituxan) has shown significant inhibition of progression of joint destruction in this highly refractory population. These differences in response rates among the same class of biologic agents, and the fact that not all patients with RA respond to biologics, indicate the heterogeneity of patients and the disease.

Thus, an individualized approach to the management of RA is needed so that each patient can receive optimal treatment, while avoiding unnecessary exposure to potentially toxic side effects and the costs of a biologic agent that may not be effective for that patient.

A recently published review (Emery P, et al. Ann Rheum Dis. 2011;70:2063-2070) examined the current evidence for markers with prognostic capabilities in RA and assessed their potential in predicting individual treatment responses to biologic agents and in­forming clinical practice. The markers that were examined included patient clinical characteristics, genetic markers, and protein molecular biomarkers. Several studies from patient registries have shown that high levels of disability at baseline and being a smoker are predictive of a poor response to TNF antagonists. More­over, lower baseline Disease Activity Score in 28 joints, Health Assessment Question­naire scores, and concurrent use of conventional DMARDs appear to be associated with improved TNF inhibitor responses. Age, sex, disease duration, and the previous number of DMARDs used were not predictive of TNF inhibitor response. It is unclear whether any of the baseline characteristics are useful as potential markers of response or simply represent prognostic indicators.

The recognition that variation in response to treatment may be linked to genetic traits has led to the study of genetic markers as predictors of response to treatment. Such analyses provide a way of using genetics in a fully translational approach, from both a screening and therapeutic response perspective to informing clinical practice. Specifically, polymorphisms in genes encoding for TNFα, the major histocompatibility region, the p38 network, STAT4, PTPN22, PAD14, CTLA-4, Traf1/C5, and FC

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